siRNA Transfection with Calcium Phosphate Nanoparticles Stabilized with PEGylated Chelators

Authors

  • Elisabeth V. Giger,

    1. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
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  • Bastien Castagner,

    1. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
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  • Johanna Räikkönen,

    1. School of Pharmacy, Faculty of Health Sciences and Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
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  • Jukka Mönkkönen,

    1. School of Pharmacy, Faculty of Health Sciences and Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland
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  • Jean-Christophe Leroux

    Corresponding author
    1. Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland
    • Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
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Abstract

Despite the enormous therapeutic potential of siRNAs, their delivery is still problematic due to unfavorable biodistribution profiles and poor intracellular bioavailability. Calcium phosphate co-precipitate has been used for nearly 40 years for in vitro transfection due to its non-toxic nature and simplicity of preparation. However, rapid particle growth has largely prevented the translation of this method for in vivo purposes. It has recently been shown that bisphosphonate derivatives can physically stabilize calcium phosphate nanoparticles while still allowing for efficient cell transfection with plasmid DNA. Herein, two novel PEGylated chelating agents (PEG-alendronate and PEG-inositolpentakisphosphate) with enhanced stabilizing properties are introduced, and it is demonstrated that the bisphosphonate-stabilized nanoparticles can efficiently deliver siRNA in vitro. The nanoparticles are mainly taken up by clathrin-dependent endocytosis, and acidification of the endosomal compartment is required to release the entrapped siRNA into the cytosol. Furthermore, particle uptake enhances the inhibition of the mevalonate pathway by the bisphosphonate in macrophages.

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